tbuckley/cabot-search huggingface dataset:
Targeting T-cell malignancies using allogeneic double-negative CD4-CAR-T cells
Authors: Karen Kai-Lin Fang, Jongbok Lee, Ismat Khatri, Yoosu Na, Li Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Patients with relapsed/refractory T-cell malignancies have limited treatment options. The use of chimeric antigen receptor (CAR)-T cell therapy for T-cell malignancies is challenging due to possible blast contamination of autologous T-cell products and fratricide of CAR-T cells targeting T-lineage antigens. Recently, allogeneic double-negative T cells (DNTs) have been shown to be safe as an off-the-shelf adoptive cell therapy and to be amendable for CAR transduction. Here, we explore the antitumor activity of allogeneic DNTs against T-cell malignancies and the potential of using anti-CD4-CAR (CAR4)-DNTs as adoptive cell therapy for T-cell malignancies. Methods Healthy donor-derived allogeneic DNTs were ex vivo expanded with or without CAR4 transduction. The antitumor activity of DNTs and CAR4-DNTs against T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) were examined using flow cytometry-based cytotoxicity assays and xenograft models. Mechanisms of action were investigated using transwell assays and blocking assays. Results Allogeneic DNTs induced endogenous antitumor cytotoxicity against T-ALL and PTCL in vitro, but high doses of DNTs were required to attain therapeutic effects in vivo. The potency of DNTs against T-cell malignancies was significantly enhanced by transducing DNTs with a third-generation CAR4. CAR4-DNTs were manufactured without fratricide and showed superior cytotoxicity against CD4 + T-ALL and PTCL in vitro and in vivo relative to empty-vector transduced-DNTs. CAR4-DNTs eliminated T-ALL and PTCL cell lines and primary T-ALL blasts in vitro. CAR4-DNTs effectively infiltrated tumors, delayed tumor progression, and prolonged the survival of T-ALL and PTCL xenografts. Further, pretreatment of CAR4-DNTs with PI3Kδ inhibitor idelalisib promoted memory phenotype of CAR4-DNTs and enhanced their persistence and antileukemic efficacy in vivo. Mechanistically, LFA-1, NKG2D, and perforin/granzyme B degranulation pathways were involved in the DNT-mediated and CAR4-DNT-mediated killing of T-ALL and PTCL. Conclusions These results demonstrate that CAR4-DNTs can effectively target T-ALL and PTCL and support allogeneic CAR4-DNTs as adoptive cell therapy for T-cell malignancies.
Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis
Authors: Nian Liu, Mingjie Yan, Qian Tao, Jie Wu, Jing Chen, Xiang Chen, Cong Peng
Journal: Journal for ImmunoTherapy of Cancer (2023)

anti-Programmed Death-1 (anti-PD-1) immunotherapy has shown promising manifestation in improving the survival rate of patients with advanced melanoma, with its efficacy closely linked to Programmed cell death-Ligand 1 (PD-L1) expression. However, low clinical efficacy and drug resistance remain major challenges. Although the metabolic alterations from tricarboxylic acid (TCA) cycle to glycolysis is a hallmark in cancer cells, accumulating evidence demonstrating TCA cycle plays critical roles in both tumorigenesis and treatment.The plasma levels of metabolites in patients with melanoma were measured by nuclear magnetic resonance (NMR) spectroscopy. The effect of pyruvate dehydrogenase subunit 1 (PDHA1) and oxoglutarate dehydrogenase (OGDH) on immunotherapy was performed by B16F10 tumor-bearing mice. Flow cytometry analyzed the immune microenvironment. RNA sequencing analyzed the global transcriptome alterations in CPI613-treated melanoma cells. The regulation of PD-L1 and glycolysis by PDHA1/OGDH-ATF3 signaling were confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, dual-luciferase reporter gene, Chromatin immunoprecipitation (ChIP)-quantitative PCR and Seahorse assay. The relationship between PDHA1/OGDH-ATF3-glycolysis and the efficacy of melanoma anti-PD-1 immunotherapy was verified in the clinical database and single-cell RNA-seq (ScRNA-Seq).In our study, the results showed that significant alterations in metabolites associated with glycolysis and the TCA cycle in plasma of patients with melanoma through NMR technique, and then, PDHA1 and OGDH, key enzymes for regulation TCA cycle, were remarkable raised in melanoma and negatively related to anti-PD-1 efficacy through clinical database analysis as well as ScRNA-Seq. Inhibition of PDHA1 and OGDH by either shRNA or pharmacological inhibitor by CPI613 dramatically attenuated melanoma progression as well as improved the therapeutic efficacy of anti-PD-1 against melanoma. Most importantly, suppression of TCA cycle remarkably raises PD-L1 expression and glycolysis flux through AMPK-CREB-ATF3 signaling.Taken together, our results demonstrated the role of TCA cycle in immune checkpoint blockade and provided a novel combination strategy for anti-PD-1 immunotherapy in melanoma treatment.
Synergic prognostic value of 3D CT scan subcutaneous fat and muscle masses for immunotherapy-treated cancer
Authors: Pierre Decazes, Samy Ammari, Younes Belkouchi, Léo Mottay, Littisha Lawrance, Antoine de Prévia, Hugues Talbot, Siham Farhane, Paul-Henry Cournède, Aurelien Marabelle, Florian Guisier, David Planchard, Tony Ibrahim, Caroline Robert, Fabrice Barlesi, Pierre Vera, Nathalie Lassau
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy. Methods We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis. Results In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p&lt;0.001) for patients with low SFM (&lt;3.95 kg/m 2 ), low FBM (&lt;3.26 kg/m 2 ), low VFM (&lt;0.91 kg/m 2 ), low MBM (&lt;5.85 kg/m 2 ) and low BMI (&lt;24.97 kg/m 2 ). The same parameters were significant in the Cox univariate analysis (p&lt;0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p&lt;0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (&lt;5.22 kg/m 2 ) and MBM (&lt;6.86 kg/m 2 ) (p&lt;0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029). Conclusions 3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value.
Sensory interventions to relieve dyspnoea in critically ill mechanically ventilated patients
Authors: Côme Bureau, Marie-Cécile Niérat, Maxens Decavèle, Isabelle Rivals, Laurence Dangers, Alexandra Beurton, Sara Virolle, Robin Deleris, Julie Delemazure, Julien Mayaux, Capucine Morélot-Panzini, Martin Dres, Thomas Similowski, Alexandre Demoule
Journal: European Respiratory Journal (2023)

Background In critically ill patients receiving mechanical ventilation, dyspnoea is frequent, severe and associated with an increased risk of neuropsychological sequelae. We evaluated the efficacy of sensory interventions targeting the brain rather than the respiratory system to relieve dyspnoea in mechanically ventilated patients. Methods Patients receiving mechanical ventilation for ≥48 h and reporting dyspnoea (unidimensional dyspnoea visual analogue scale (Dyspnoea-VAS)) first underwent increased pressure support and then, in random order, auditory stimulation (relaxing music versus pink noise) and air flux stimulation (facial versus lower limb). Treatment responses were assessed using Dyspnoea-VAS, the Multidimensional Dyspnea Profile and measures of the neural drive to breathe (airway occlusion pressure ( P 0.1 ) and electromyography of inspiratory muscles). Results We included 46 patients (tracheotomy or intubation n=37; noninvasive ventilation n=9). Increasing pressure support decreased Dyspnoea-VAS by median 40 mm (p&lt;0.001). Exposure to music decreased Dyspnoea-VAS compared with exposure to pink noise by median 40 mm (p&lt;0.001). Exposure to facial air flux decreased Dyspnoea-VAS compared with limb air flux by median 30 mm (p&lt;0.001). Increasing pressure support, but not music exposure and facial air flux, reduced P 0.1 by median 3.3 cmH 2 O (p&lt;0.001). Conclusions In mechanically ventilated patients, sensory interventions can modulate the processing of respiratory signals by the brain irrespective of the intensity of the neural drive to breathe. It should therefore be possible to alleviate dyspnoea without resorting to pharmacological interventions or having to infringe the constraints of mechanical ventilation lung protection strategies by increasing ventilatory support.
Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts
Authors: Margaret Veitch, Kimberly Beaumont, Rebecca Pouwer, Hui Yi Chew, Ian H Frazer, H Peter Soyer, Scott Campbell, Brian W Dymock, Andrew Harvey, Terrie-Anne Cock, James W Wells
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. Methods In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in “regressor” models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. Results Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. Conclusions Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
Real-world cohort evaluation of the impact of the antifibrotics in patients with idiopathic pulmonary fibrosis
Authors: Timothy M. Dempsey, Viengneesee Thao, David A. Helfinstine, Yu-Hui H. Chang, Lindsey Sangaralingham, Andrew H. Limper
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Consistent with prior observational studies, pirfenidone and nintedanib were observed to have reduced risk of mortality and hospitalisations in patients with IPF in this large US Medicare dataset. The result holds after accounting for "immortal time bias".</b>https://bit.ly/3YWFyTK
MRI pulmonary artery flow detects lung vascular pathology in preterms with lung disease
Authors: Friederike Häfner, Alida Kindt, Kathrin Strobl, Kai Förster, Motaharehsadat Heydarian, Erika Gonzalez, Benjamin Schubert, Yvonne Kraus, Robert Dalla Pozza, Andreas W. Flemmer, Birgit Ertl-Wagner, Olaf Dietrich, Sophia Stoecklein, Khodr Tello, Anne Hilgendorff
Journal: European Respiratory Journal (2023)

Background Pulmonary vascular disease (PVD) affects the majority of preterm neonates with bronchopulmonary dysplasia (BPD) and significantly determines long-term mortality through undetected progression into pulmonary hypertension. Our objectives were to associate characteristics of pulmonary artery (PA) flow and cardiac function with BPD-associated PVD near term using advanced magnetic resonance imaging (MRI) for improved risk stratification. Methods Preterms &lt;32 weeks postmenstrual age (PMA) with/without BPD were clinically monitored including standard echocardiography and prospectively enrolled for 3 T MRI in spontaneous sleep near term (AIRR (Attention to Infants at Respiratory Risks) study). Semi-manual PA flow quantification (phase-contrast MRI; no BPD n=28, mild BPD n=35 and moderate/severe BPD n=25) was complemented by cardiac function assessment (cine MRI). Results We identified abnormalities in PA flow and cardiac function, i.e. increased net forward volume right/left ratio, decreased mean relative area change and pathological right end-diastolic volume, to sensitively detect BPD-associated PVD while correcting for PMA (leave-one-out area under the curve 0.88, sensitivity 0.80 and specificity 0.81). We linked these changes to increased right ventricular (RV) afterload (RV–arterial coupling (p=0.02), PA mid-systolic notching (t2; p=0.015) and cardiac index (p=1.67×10 −8 )) and correlated echocardiographic findings. Identified in moderate/severe BPD, we successfully applied the PA flow model in heterogeneous mild BPD cases, demonstrating strong correlation of PVD probability with indicators of BPD severity, i.e. duration of mechanical ventilation (r s =0.63, p=2.20×10 −4 ) and oxygen supplementation (r s =0.60, p=6.00×10 −4 ). Conclusions Abnormalities in MRI PA flow and cardiac function exhibit significant, synergistic potential to detect BPD-associated PVD, advancing the possibilities of risk-adapted monitoring.
Mutational topography reflects clinical neuroblastoma heterogeneity
Authors: Elias Rodriguez-Fos, Mercè Planas-Fèlix, Martin Burkert, Montserrat Puiggròs, Joern Toedling, Nina Thiessen, Eric Blanc, Annabell Szymansky, Falk Hertwig, Naveed Ishaque, Dieter Beule, David Torrents, Angelika Eggert, Richard P. Koche, Roland F. Schwarz, Kerstin Haase, Johannes H. Schulte, Anton G. Henssen
Journal: Cell Genomics (2023)

Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processes driving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes. Whereas high-risk
NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
Authors: Rui Zhan, Xia Meng, Dongping Tian, Jie Xu, Hongtu Cui, Jialei Yang, Yangkai Xu, Mingming Shi, Jing Xue, Weiwei Yu, Gaofei Hu, Ke Li, Xiaoxiao Ge, Qi Zhang, Mingming Zhao, Jianyong Du, Xin Guo, Wenli Xu, Yang Gao, Changyu Yao, Fan Chen, Yue Chen, Wenxin Shan, Yujie Zhu, Liang Ji, Bing Pan, Yan Yu, Wenguang Li, Xuyang Zhao, Qihua He, Xiaohui Liu, Yue Huang, Shengyou Liao, Bin Zhou, Dehua Chui, Y. Eugene Chen, Zheng Sun, Erdan Dong, Yongjun Wang, Lemin Zheng
Journal: Neuron (2023)
CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1
Authors: Beiping Miao, Zhaoqing Hu, Riccardo Mezzadra, Lotte Hoeijmakers, Astrid Fauster, Shangce Du, Zhi Yang, Melanie Sator-Schmitt, Helena Engel, Xueshen Li, Caroline Broderick, Guangzhi Jin, Raquel Gomez-Eerland, Lisette Rozeman, Xin Lei, Hitoshi Matsuo, Chen Yang, Ingrid Hofland, Dennis Peters, Annegien Broeks, Elke Laport, Annika Fitz, Xiyue Zhao, Mohamed A.A. Mahmoud, Xiujian Ma, Sandrine Sander, Hai-kun Liu, Guoliang Cui, Yu Gan, Wei Wu, Yanling Xiao, Albert J.R. Heck, Wenxian Guan, Scott W. Lowe, Hugo M. Horlings, Cun Wang, Thijn R. Brummelkamp, Christian U. Blank, Ton N.M. Schumacher, Chong Sun
Journal: Cancer Cell (2023)

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.
Associations between lipid profiles and late‐life cognitive impairment among oldest‐old and centenarian adults
Authors: Yujian Chen, Kaidi Yang, Ya Huang, Xuejiao Wang, Yali Zhao, Ping Ping, Shasha Guan, Shihui Fu
Journal: MedComm (2023)

Dyslipidemia and cognitive impairment are common among old adults and the occurrence of them rises exponentially with increasing age. Evidences of the relationships between serum lipids and cognitive impairment are inconsistent or equivocal among older adults. This study aimed to investigate the associations between lipid profiles and late-life cognitive impairment among oldest-old and centenarian adults. In this cross-sectional study, serum lipids were biochemically measured among 606 oldest-old adults and 653 centenarians, and cognitive function was evaluated using mini-mental state examination (MMSE). Multivariate linear and logistic regression analyses were performed to explore the associations between serum lipids and cognitive impairment. Results showed participants with cognitive impairment had lower total cholesterol (TC) levels compared with those without cognitive impairment (
Sex and gender differences in intensive care medicine
Authors: Hamid Merdji, Micah T. Long, Marlies Ostermann, Margaret Herridge, Sheila N. Myatra, Silvia De Rosa, Victoria Metaxa, Katarzyna Kotfis, Chiara Robba, Audrey De Jong, Julie Helms, Caroline E. Gebhard
Journal: Intensive Care Medicine (2023)

Despite significant advancements in critical care medicine, limited attention has been given to sex and gender disparities in management and outcomes of patients admitted to the intensive care unit (ICU). While "sex" pertains to biological and physiological characteristics, such as reproductive organs, chromosomes and sex hormones, "gender" refers more to sociocultural roles and human behavior. Unfortunately, data on gender-related topics in the ICU are lacking. Consequently, data on sex and gender-related differences in admission to the ICU, clinical course, length of stay, mortality, and post-ICU burdens, are often inconsistent. Moreover, when examining specific diagnoses in the ICU, variations can be observed in epidemiology, pathophysiology, presentation, severity, and treatment response due to the distinct impact of sex hormones on the immune and cardiovascular systems. In this narrative review, we highlight the influence of sex and gender on the clinical course, management, and outcomes of the most encountered intensive care conditions, in addition to the potential co-existence of unconscious biases which may also impact critical illness. Diagnoses with a known sex predilection will be discussed within the context of underlying sex differences in physiology, anatomy, and pharmacology with the goal of identifying areas where clinical improvement is needed. To optimize patient care and outcomes, it is crucial to comprehend and address sex and gender differences in the ICU setting and personalize management accordingly to ensure equitable, patient-centered care. Future research should focus on elucidating the underlying mechanisms driving sex and gender disparities, as well as exploring targeted interventions to mitigate these disparities and improve outcomes for all critically ill patients.